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      Knockdown of the survival motor neuron (Smn) protein in zebrafish causes defects in motor axon outgrowth and pathfinding

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          Abstract

          Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by a loss of α motoneurons in the spinal cord. SMA is caused by low levels of the ubiquitously expressed survival motor neuron (Smn) protein. As it is unclear how low levels of Smn specifically affect motoneurons, we have modeled SMA in zebrafish, a vertebrate model organism with well-characterized motoneuron development. Using antisense morpholinos to reduce Smn levels throughout the entire embryo, we found motor axon–specific pathfinding defects. Reduction of Smn in individual motoneurons revealed that smn is acting cell autonomously. These results show for the first time, in vivo, that Smn functions in motor axon development and suggest that these early developmental defects may lead to subsequent motoneuron loss.

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          Structure of the zebrafish snail1 gene and its expression in wild-type, spadetail and no tail mutant embryos.

          C Thisse, T Schilling, J Postlethwait … (1993)
          Mesoderm formation is critical for the establishment of the animal body plan and in Drosophila requires the snail gene. This report concerns the cloning and expression pattern of the structurally similar gene snail1 from zebrafish. In situ hybridization shows that the quantity of snail1 RNA increases at the margin of the blastoderm in cells that involute during gastrulation. As gastrulation begins, snail1 RNA disappears from the dorsal axial mesoderm and becomes restricted to the paraxial mesoderm and the tail bud. snail1 RNA increases in cells that define the posterior border of each somite and then disappears when somitic cells differentiate. Later in development, expression appears in cephalic neural crest derivatives. Many snail1-expressing cells were missing from mutant spadetail embryos and the quantity of snail1 RNA was greatly reduced in mutant no tail embryos. The work presented here suggests that snail1 is involved in morphogenetic events during gastrulation, somitogenesis and development of the cephalic neural crest, and that no tail may act as a positive regulator of snail1.
          Article 0 comments Cited 152 times – based on 0 reviews     Review now
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            Headwaters of the zebrafish -- emergence of a new model vertebrate.

            David Grunwald, Judith Eisen (2002)
            The understanding of vertebrate development has advanced considerably in recent years, primarily due to the study of a few model organisms. The zebrafish, the newest of these models, has risen to prominence because both genetic and experimental embryological methods can be easily applied to this animal. The combination of approaches has proven powerful, yielding insights into the formation and function of individual tissues, organ systems and neural networks, and into human disease mechanisms. Here, we provide a personal perspective on the history of zebrafish research, from the assembly of the first genetic and embryological tools through to sequencing of the genome.
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              The survival motor neuron protein in spinal muscular atrophy.

              D D Coovert, T. Le, P E McAndrew … (1997)
              The 38 kDa survival motor neuron (SMN) protein is encoded by two ubiquitously expressed genes: telomeric SMN (SMN(T)) and centromeric SMN (SMN(C)). Mutations in SMN(T), but not SMN(C), cause proximal spinal muscular atrophy (SMA), an autosomal recessive disorder that results in loss of motor neurons. SMN is found in the cytoplasm and nucleus. The nuclear form is located in structures termed gems. Using a panel of anti-SMN antibodies, we demonstrate that the SMN protein is expressed from both the SMN(T) and SMN(C) genes. Western blot analysis of fibroblasts from SMA patients with various clinical severities of SMA showed a moderate reduction in the amount of SMN protein, particularly in type I (most severe) patients. Immunocytochemical analysis of SMA patient fibroblasts indicates a significant reduction in the number of gems in type I SMA patients and a correlation of the number of gems with clinical severity. This correlation to phenotype using primary fibroblasts may serve as a useful diagnostic tool in an easily accessible tissue. SMN is expressed at high levels in brain, kidney and liver, moderate levels in skeletal and cardiac muscle, and low levels in fibroblasts and lymphocytes. In SMA patients, the SMN level was moderately reduced in muscle and lymphoblasts. In contrast, SMN was expressed at high levels in spinal cord from normals and non-SMA disease controls, but was reduced 100-fold in spinal cord from type I patients. The marked reduction of SMN in type I SMA spinal cords is consistent with the features of this motor neuron disease. We suggest that disruption of SMN(T) in type I patients results in loss of SMN from motor neurons, resulting in the degeneration of these neurons.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Cell Biol
                Title: The Journal of Cell Biology
                Publisher: The Rockefeller University Press
                ISSN (Print): 0021-9525
                ISSN (Electronic): 1540-8140
                Publication date (Print): 1 September 2003
                Volume: 162
                Issue: 5
                Pages: 919-932
                Affiliations
                [1 ]Center for Molecular Neurobiology, Cellular, and Developmental Biology Program
                [2 ]Molecular, Cellular, and Developmental Biology Program
                [3 ]Department of Neurology, The Ohio State University, Columbus, OH 43210
                [4 ]Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH 43210
                [5 ]Department of Molecular Genetics, The Ohio State University, Columbus, OH 43210
                [6 ]Department of Neuroscience, The Ohio State University, Columbus, OH 43210
                Author notes

                Address correspondence to Christine E. Beattie, Center for Molecular Neurobiology, The Ohio State University, 115 Rightmire Hall, 1060 Carmack Road, Columbus, OH 43210. Tel.: (614) 292-5113. Fax: (614) 292-5379. email: beattie.24@ 123456osu.edu

                Article
                Publisher ID: 200303168
                DOI: 10.1083/jcb.200303168
                PMC ID: 1761110
                PubMed ID: 12952942
                SO-VID: d3176e49-ed0d-40d1-b03a-4eec51253fe0
                Copyright © Copyright © 2003, The Rockefeller University Press
                History
                Date received : 26 March 2003
                Date accepted : 14 July 2003
                Categories
                Subject: Article

                ScienceOpen disciplines: Cell biology
                Keywords: sma; smn; motoneurons; zebrafish; morpholino
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: sma; smn; motoneurons; zebrafish; morpholino

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